JP2000506497A - 平滑筋弛緩活性および/またはマスト細胞安定化活性および/または抗炎症活性を有するインダン化合物 - Google Patents
平滑筋弛緩活性および/またはマスト細胞安定化活性および/または抗炎症活性を有するインダン化合物Info
- Publication number
- JP2000506497A JP2000506497A JP9521127A JP52112797A JP2000506497A JP 2000506497 A JP2000506497 A JP 2000506497A JP 9521127 A JP9521127 A JP 9521127A JP 52112797 A JP52112797 A JP 52112797A JP 2000506497 A JP2000506497 A JP 2000506497A
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- Prior art keywords
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- compound
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- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 210000003630 histaminocyte Anatomy 0.000 title claims abstract description 19
- 210000002460 smooth muscle Anatomy 0.000 title claims abstract description 11
- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 10
- 230000002040 relaxant effect Effects 0.000 title claims abstract description 8
- 230000000087 stabilizing effect Effects 0.000 title claims description 11
- 125000003392 indanyl group Chemical class C1(CCC2=CC=CC=C12)* 0.000 title abstract 2
- -1 acetoxy, carboxy Chemical group 0.000 claims abstract description 47
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 150000002923 oximes Chemical class 0.000 claims abstract description 10
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000002252 acyl group Chemical group 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 229910002651 NO3 Inorganic materials 0.000 claims abstract description 5
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims abstract description 5
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 5
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 150000002825 nitriles Chemical class 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 5
- 125000001174 sulfone group Chemical group 0.000 claims abstract description 5
- 150000003573 thiols Chemical class 0.000 claims abstract description 5
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical group SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 4
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims abstract description 4
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003375 sulfoxide group Chemical group 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 3
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims abstract description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 121
- 238000000034 method Methods 0.000 claims description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 230000009467 reduction Effects 0.000 claims description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 150000002576 ketones Chemical group 0.000 claims description 13
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002841 Lewis acid Substances 0.000 claims description 7
- 150000007517 lewis acids Chemical class 0.000 claims description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- BSAIUCUXHVGXNK-UHFFFAOYSA-N 3-bromo-2,3-dihydroinden-1-one Chemical compound C1=CC=C2C(Br)CC(=O)C2=C1 BSAIUCUXHVGXNK-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000005597 hydrazone group Chemical group 0.000 claims description 4
- 125000005462 imide group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- 238000010934 O-alkylation reaction Methods 0.000 claims description 3
- 238000009739 binding Methods 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 3
- 238000011911 α-alkylation Methods 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 230000006181 N-acylation Effects 0.000 claims description 2
- 238000007126 N-alkylation reaction Methods 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims 5
- 238000010168 coupling process Methods 0.000 claims 5
- 238000005859 coupling reaction Methods 0.000 claims 5
- 239000003638 chemical reducing agent Substances 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims 2
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 claims 1
- LMHHFZAXSANGGM-UHFFFAOYSA-N 2-aminoindane Chemical class C1=CC=C2CC(N)CC2=C1 LMHHFZAXSANGGM-UHFFFAOYSA-N 0.000 claims 1
- UXVCSPSWUNMPMT-UHFFFAOYSA-N 2-bromo-2,3-dihydroinden-1-one Chemical compound C1=CC=C2C(=O)C(Br)CC2=C1 UXVCSPSWUNMPMT-UHFFFAOYSA-N 0.000 claims 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 1
- 230000000397 acetylating effect Effects 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 239000011260 aqueous acid Substances 0.000 claims 1
- 150000001728 carbonyl compounds Chemical class 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- YIAPLDFPUUJILH-UHFFFAOYSA-N indan-1-ol Chemical class C1=CC=C2C(O)CCC2=C1 YIAPLDFPUUJILH-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 claims 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims 1
- HTBVGZAVHBZXMS-UHFFFAOYSA-N lithium;tris[(2-methylpropan-2-yl)oxy]alumane Chemical compound [Li].[Al+3].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] HTBVGZAVHBZXMS-UHFFFAOYSA-N 0.000 claims 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims 1
- 235000017281 sodium acetate Nutrition 0.000 claims 1
- 239000001632 sodium acetate Substances 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims 1
- MDDPTCUZZASZIQ-UHFFFAOYSA-N tris[(2-methylpropan-2-yl)oxy]alumane Chemical compound [Al+3].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] MDDPTCUZZASZIQ-UHFFFAOYSA-N 0.000 claims 1
- 239000011995 wilkinson's catalyst Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- 239000003381 stabilizer Substances 0.000 abstract description 5
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- KXXGUOQSUCTRNO-UHFFFAOYSA-N N(N)N(N)C#N Chemical compound N(N)N(N)C#N KXXGUOQSUCTRNO-UHFFFAOYSA-N 0.000 abstract 1
- 150000007857 hydrazones Chemical class 0.000 abstract 1
- 150000003949 imides Chemical class 0.000 abstract 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
- 238000006243 chemical reaction Methods 0.000 description 39
- 239000000047 product Substances 0.000 description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 238000006722 reduction reaction Methods 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 15
- 229960001340 histamine Drugs 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 8
- 206010030113 Oedema Diseases 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 238000010828 elution Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000001110 calcium chloride Substances 0.000 description 5
- 229910001628 calcium chloride Inorganic materials 0.000 description 5
- 235000011148 calcium chloride Nutrition 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical class O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 5
- 239000001103 potassium chloride Substances 0.000 description 5
- 235000011164 potassium chloride Nutrition 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 240000001307 Myosotis scorpioides Species 0.000 description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 230000008602 contraction Effects 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 235000019799 monosodium phosphate Nutrition 0.000 description 3
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 238000005694 sulfonylation reaction Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- BMZXRZWCNDBOOU-UHFFFAOYSA-N 3-(cyclopentylamino)-2,3-dihydroinden-1-one Chemical compound C12=CC=CC=C2C(=O)CC1NC1CCCC1 BMZXRZWCNDBOOU-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
- C07C13/45—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing nine carbon atoms
- C07C13/465—Indenes; Completely or partially hydrogenated indenes
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.次式: (式中、 式7において、R2〜R13および 式8において、R1およびR3〜R13が、H、ハロゲン、ヒドロキシ、アルコキシ、 アリールオキシ、アセトキシ、カルボキシ、アルキルカルボニル、ヒドロカルボ ニル、アミノ、アミド、アルキルアミノ、ヒドロキシアミノ、酸化アミン基、ア ゾ基、シアノ、ヒドラジノ基、ヒドラジン基、ヒドラゾン基、イミド基、イミノ エーテル基、ウレイル基、オキシム、ニトロ、ニトレート、ニトライト、ニトロ ソ基、ニトリル、N、OまたはSの一つ以上を含有するヘテロ原子を含有する複 素環式基、アラルキル基、モノおよびポリベンゾイドアリール基、置換アリール 基、チオール、チオウレイル、フェニルチオール基、硫酸基、スルホキシド基、 スルホン基、飽和または不飽和であってよい1〜10炭素原子を含有するアルキル または3〜8炭素原子を含有するシクロアルキル基、飽和または不飽和であってよ い置換アルキルまたはシクロアルキル基の1つ又はこれらの同一もしくは異なる 2つ以上から選択され、 Xは結合、O、またはNR(Rはアシル、アルキルまたはスルホネート基である )、S、SOまたはSO2であり、 XはR8およびR13;R8およびR12のいずれかの結合であり;またはR8およびR9は ともに 二重結合を表してもよいときに、 式7において、R2、1R2 R3、1R3;R9、1R9;R10、1R10;R11、1R11;R12、1R12 がともにオキソを表してもよく、そして 式8において、R1、1R1;R3、1R3;R9、1R9;R10、1R10;R11、1R11;R12、1R12 はともにオキソを表してもよい)のいずれかの化合物、その薬学的に許容され る塩、エステル、アミド、溶媒和物および異性体。 2.前記アルキルまたはシクロアルキルが、ハロゲン、オキソ、ヒドロキシ、アル コキシ、アリールオキシ、アセトキシ、カルボキシ、カルボニル、アミノ、アミ ド、アルキルアミノ、ヒドロキシアミノ、酸化アミン基、アゾ基、シアノ、ヒド ラジノ基、ヒドラジド基、ヒドラゾン基、イミド基、イミノエーテル基、ウレイ ル基、オキシム、ニトロ、ニトレート、ニトライト、ニトロソ基、ニトリル、複 素環式基、アラルキル基、モノおよびポリベンゾイドアリール基、置換アリール 基、チオール、チオウレイル、フェニルチオール基、スルホン酸基、スルホニル 基およびスルホン基の1つ又はこれらの同一もしくは異なる2つ以上で置換され ている請求項1記載の化合物。 3.複素環式基が一つ以上のN、OまたはSを含有するヘテロ原子から選択される 請求項1または2に記載の化合物。 4.式7において、R4〜R7が水素を表す請求項1〜3いずれかに記載の化合物。 5.式7において、R10および/またはR11が水素を表す請求項1〜4いずれかに記載 の化合物。 6.式7において、R2、1R2がH、OHを表す請求項1〜5いずれかに記載の化合物。 7.式7において、Xが結合を表す請求項1〜6いずれかに記載の化合物。 8.式7において、R13がベンジルを表す請求項1〜7いずれかに記載の化合物。 9.R8およびR9またはR8およびR12がともに二重結合を表す請求項1〜8いずれかに 記載の化合物。 10.式7において、R3、1R3がともにOを表す請求項1〜5いずれかに記載の化合物 。 11.Xがアルキル基により置換されたNを表す請求項1〜5または10いずれかに記 載の化合物。 12.式7においてXが二重結合を表す請求項1〜5いずれかに記載の化合物。 13.式7において、R2、1R2がともにOを表す請求項1〜5または12いずれかに記載 の化合物。 14.式8において、R4〜R7が水素を表す請求項1〜5いずれかに記載の化合物。 15.式8において、R11および/またはR12が水素を表す請求項1〜3または14いず れかに記載 の化合物。 16.式8において、R8およびR9またはR8およびR12がともに二重結合を表す請求項 1〜3または14または15いずれかに記載の化合物。 17.式8において、R1、1R2がH、OHを表す請求項1〜3または14〜16いずれかに記 載の化合物。 18.式8において、R13がベンジルを表す請求項1〜3、または14〜17いずれかに記 載の化合物。 19.式8において、Xが結合を表す請求項1〜3または14〜18いずれかに記載の化 合物。 20.式8において、R1、1R1がともにOを表す請求項1〜3、14または15いずれかに 記載の化合物。 21.式8において、Xがアルキルにより置換されたNを表す請求項1〜13、14、15 または20いずれかに記載の化合物。 22.式8においてXが二重結合を表す請求項1〜3、14または15いずれかに記載の 化合物。 23.R1、1R1がともにOを表す請求項1〜3、14、15または22いずれかに記載の化合 物。 24.XがNRであり、ここでRがアシルである請求項1〜3、14または15いずれかに 記載の化合物。 25.R1、1R1がともにOを表す請求項1〜3、14、15または24いずれかに記載の化合 物。 26.本明細書中の付録2に挙げられた化合物のいずれかから選択される化合物。 27.実質的に本明細書中の実施例に記載された化合物。 28.請求項1〜27いずれかに記載された式7または8の化合物と医薬的に許容さ れるキャリヤとからなる医薬組成物。 29.前記の実施例に実質的に記載された医薬組成物。 30.平滑筋弛緩活性および/またはマスト細胞安定化活性および/または抗炎症 活性を得るべく請求項1〜27いずれかに記載された式7または8の化合物の使用 。 31.実質的に本明細書中の実施例に記載された使用。 32.平滑筋弛緩活性および/またはマスト細胞安定化活性および/または抗炎症 活性を得るべく請求項1〜27いずれかに記載された式7または8の化合物。 33.平滑筋弛緩活性および/またはマスト細胞安定化活性および/または抗炎症 活性を得るべく請求項1〜27いずれかに記載された式7または8の効果的な量の 化合物を患者に投与することによる予防または治療方法。 34.インダン-1-オンをトリ-tert-ブトキシドアルミニウムと反応させることによ る請求項1の化合物の調製方法。 35.ジイソプロピルアミドリチウムまたはtert-ブトキシドカリウムを特に用いて 、ためにα,βエノンをアルキル化してα-アルキル-β、αエノンを得ることに よる請求項1の化合物の調製方法。 36.HCl等の酸水溶液をも含む触媒、殊に活性化木炭上のパラジウムを特に用いて 、二重結合および/またはケトン官能基の還元による請求項1の化合物の調製方 法。 37.ホウ水素化ナトリウムによるケトン官能基の還元による請求項1の化合物の 調製方法。 38.ヒドラジン水和物を用いるケトン官能基の還元による請求項1の化合物の調 製方法。 39.シアノホウ水素化ナトリウムを用いるケトン官能基の還元による請求項1の 化合物の調製方法。 40.活性化炭素上の5%パラジウムによるα,βエノン二重結合の還元または異性 化による請求項1の化合物の調製方法。 41.Wilkinsons触媒を用いて5員環の外側のc=cの還元による請求項1の化合物の 調製方法。 42.ルイス酸を用いて、インダノンのシリルエノールエーテルを同一または異な るインダノンの対応するジメチルアセタールに結合させることによる請求項1の 化合物の調製方法。 43.ルイス酸がTMSトリフレートである請求項42記載の製法。 44.シリルエノールエーテルと異なるインダンのジメチルアセタールとの結合か ら得られたメチルエーテルからメタノールを脱離する工程を包含する請求項42ま たは43記載の製法。 45.メタノールがトリフル酸を加えることにより脱離される請求項44記載の製法 。 46.ルイス酸を用いて3-ブロモインダン-1-オンをシリルエノールエーテルに結合 させる過程からなる請求項1の化合物の調製方法。 47.ルイス酸がTMSトリフレートである請求項46記載の製法。 48.還元剤として水素化アルミニウムリチウムを用いることにより、または水素 化トリtertブトキシアルミニウムリチウムでの、ケトン官能基の還元による請求 項1の化合物の調製方法。 49.ルイス酸を用いて、インダノンのシリルエノール-エーテルを1-インダノンの 対応する環状ケタールまたは適当なカルボニル化合物と結合させることによる請 求項1の化合物の調製方法。 50.ルイス酸がTMSトリフレートである請求項49記載の製法。 51.3ブロモ-インダノンを1-および2-アミノ-インダン誘導体に結合させることに よる請求項1 の化合物の調製方法。 52.結合生成物のN-アルキル化またはN-アシル化の過程を包含する請求項51記 載の製法。 53.メタンスルホン酸塩化物またはメタンスルホン酸無水物を用いて1-インダノ ール誘導体を自己結合させることによる請求項1記載の化合物の調製方法。 54.請求項1の化合物のアルコール官能基のアセチル化による請求項1記載の化 合物の調製方法。 55.ピリジンもしくは酢酸ナトリウムのいずれかを塩基として用いて、特にヒド ロキシルアミン塩酸塩を用いてオキシムを形成することによる請求項1の化合物 、特に請求項1の水溶性化合物の調製方法。 56.tert-ブトキシドリチウムまたはジイソプロピルアミドリチウムのいずれかを 塩基として用いるオキシム官能基のO-アルキル化の過程を包含する請求項55記 載の製法。 57.リチウムN-ブチルを塩基として用いるベンジルオキシムエーテルのα-アル キル化の過程を包含する請求項56記載の製法。 58.水素化アルミニウムリチウムを還元剤として用いるO-ベンジルオキシムエー テルを還元する過程を包含する請求項57記載の製法。 59.実質的に本明細書中の実施例に記載された式7または8の化合物の調製方法 。 60.請求項34〜59のいずれかの製法により調製された式7または8の化合物。 61.本明細書中の実施例に記載の新規な中間体。
Applications Claiming Priority (5)
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IE950922 | 1995-12-06 | ||
IE950922 | 1995-12-06 | ||
IE960762 | 1996-10-31 | ||
IE960762 | 1996-10-31 | ||
PCT/IE1996/000082 WO1997020806A1 (en) | 1995-12-06 | 1996-12-06 | Indane compounds with smooth muscle relaxing and/or mast cell stabilising and/or anti-inflammatory activity |
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JP9521125A Ceased JP2000502328A (ja) | 1995-12-06 | 1996-12-06 | インダンダイマー化合物およびそれらの医薬的用途 |
JP9521126A Ceased JP2000502072A (ja) | 1995-12-06 | 1996-12-06 | 平滑筋弛緩および/または肥満細胞安定化および/または抗炎症作用を有するインダンダイマー(二量体)化合物 |
JP9521127A Ceased JP2000506497A (ja) | 1995-12-06 | 1996-12-06 | 平滑筋弛緩活性および/またはマスト細胞安定化活性および/または抗炎症活性を有するインダン化合物 |
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JP9521125A Ceased JP2000502328A (ja) | 1995-12-06 | 1996-12-06 | インダンダイマー化合物およびそれらの医薬的用途 |
JP9521126A Ceased JP2000502072A (ja) | 1995-12-06 | 1996-12-06 | 平滑筋弛緩および/または肥満細胞安定化および/または抗炎症作用を有するインダンダイマー(二量体)化合物 |
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US (3) | US6300376B1 (ja) |
EP (3) | EP0865419B1 (ja) |
JP (3) | JP2000502328A (ja) |
KR (2) | KR19990071978A (ja) |
AT (3) | ATE246668T1 (ja) |
AU (3) | AU1169397A (ja) |
CA (2) | CA2239694C (ja) |
DE (3) | DE69629390T2 (ja) |
DK (1) | DK0865419T3 (ja) |
GB (3) | GB2322858A (ja) |
IE (1) | IE960865A1 (ja) |
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US6225327B1 (en) | 1996-04-18 | 2001-05-01 | Alcon Laboratories, Inc. | Compounds which inhibit human conjunctival mast cell degranulation for treating ocular allergic-type complications |
JP2002510300A (ja) | 1997-06-05 | 2002-04-02 | ヴィーナンティアス・リミテッド | インダン化合物及びそれらの医薬学的使用 |
JP2001064202A (ja) * | 1999-08-25 | 2001-03-13 | Kissei Pharmaceut Co Ltd | 心不全予防治療剤 |
DE10142660A1 (de) | 2001-08-31 | 2003-03-20 | Aventis Pharma Gmbh | Verwendung von Derivaten von C2-substituierten Indan-1-ol-Systemen zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Obesitas |
DE10142722A1 (de) | 2001-08-31 | 2003-03-27 | Aventis Pharma Deutschland GmbH, 65929 Frankfurt | C2-substituierte Indan-1-one und ihre Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
DE10142666A1 (de) | 2001-08-31 | 2003-03-20 | Aventis Pharma Gmbh | Verwendung von C2-substituierten Indan-1-ol-Systemen zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Obesitas |
DE10142665B4 (de) | 2001-08-31 | 2004-05-06 | Aventis Pharma Deutschland Gmbh | C2-Disubstituierte Indan-1-one und ihre Derivate |
DE10142668A1 (de) | 2001-08-31 | 2003-03-20 | Aventis Pharma Gmbh | Verwendung von C2-substituierten Indan-1-on-Systemen zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Obesitas |
DE10142662B4 (de) * | 2001-08-31 | 2004-07-08 | Aventis Pharma Deutschland Gmbh | Derivate von C2-substituierten Indan-1-ol-Systemen und ihre Verwendung als Arzneimittel |
DE10142661B4 (de) * | 2001-08-31 | 2004-06-09 | Aventis Pharma Deutschland Gmbh | Mehrfach substituierte Indan-1-ol-Systeme und ihre Verwendung als Arzneimittel |
DE10142667B4 (de) | 2001-08-31 | 2004-06-09 | Aventis Pharma Deutschland Gmbh | C2-substituierte Indan-1-ole und ihre Derivate und ihre Verwendung als Arzneimittel |
DE10142659A1 (de) | 2001-08-31 | 2003-03-20 | Aventis Pharma Gmbh | Verwendung von mehrfach substituierten Indan-1-ol. Systemen zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Obesitas |
DE10142663B4 (de) * | 2001-08-31 | 2004-08-19 | Aventis Pharma Deutschland Gmbh | C2-Disubstituierte Indan-1-ol-Systeme |
US10517839B2 (en) * | 2008-06-09 | 2019-12-31 | Cornell University | Mast cell inhibition in diseases of the retina and vitreous |
TWI537245B (zh) * | 2011-07-22 | 2016-06-11 | 維南提亞有限公司 | 用於治療自體免疫發炎疾病之化合物 |
US9260376B2 (en) | 2011-07-22 | 2016-02-16 | Venantius Limited | Compounds for use in the treatment of immune related inflammatory disease |
TWI537246B (zh) * | 2011-07-22 | 2016-06-11 | 維南提亞有限公司 | 用於治療發炎性腸病之化合物 |
EP2864279B1 (en) | 2012-05-24 | 2016-11-02 | Venantius Limited | Compounds for use in the treatment of autoimmune inflammatory disease |
EP2855416A1 (en) * | 2012-05-24 | 2015-04-08 | Venantius Limited | Indane dimers for use in the treatment of autoimmune inflammatory disease |
TWI799691B (zh) * | 2019-03-29 | 2023-04-21 | 景凱生物科技股份有限公司 | 具有側鏈烷基與烯基延伸的苯基衍生物及包括有其的藥學組合物 |
CN111533764B (zh) * | 2020-05-12 | 2023-06-06 | 杭州师范大学 | 一种利用多米诺反应制备硅氧基茚衍生物的方法 |
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DE1205537B (de) * | 1961-08-19 | 1965-11-25 | Thomae Gmbh Dr K | Verfahren zur Herstellung neuer Steroidester |
US3668258A (en) * | 1969-03-17 | 1972-06-06 | Uniroyal Inc | Sulfur-containing polyaryl polyphenolic compounds and process |
SE421305B (sv) * | 1973-10-12 | 1981-12-14 | Merck & Co Inc | Forfarande for framstellning av 1-hydroxi-5-indanyloxiettiksyror |
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1996
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